The generation of high concentrations of fine particle respirable aerosols from viscous solutions and solutions containing solutes of high molecular weight compounds and or liposomes have been fraught with difficulty, especially if these solutions have low surface tensions. Deep lung deposition is best achieved by inhaling particles having a mass median aerodynamic diameter (MMAD) of less than 4 μm. The present disclosure relates to a nozzle for creating liquid aerosols from solutions or suspensions including those of high viscosity and low surface tension together with the evaporation of the liquid from these aerosols to further reduce the particle size and to markedly increase the particle concentration in the suspending gas while reducing the total gas output to be more in balance with a desired delivery rate for particle collection, as well as their delivery to animals and humans.
Acute respiratory distress syndrome, ARDS, including acute lung injury, ALI, are of multifactorial etiology and afflict 190,000 Americans each year including 18% of all ventilated patients. Despite sophisticated intensive care, the mortality rate ranges between 15 and 72% with a mean of 43%. Patients with ARDS have impaired surfactant function and continued inflammation-induced inactivation of surfactant indicating that a single treatment with surfactant is likely inadequate. Surfactant delivery to patients with ARDS demonstrates that instillation of surfactant may improve oxygenation for ≥120 hours. However liquid bolus administration of surfactant results in a high rate of adverse effects and thus cannot be considered an effective adjunctive therapy in patients with acute lung injury. Multiple boluses of intrapulmonary instillations of surfactant are traumatic for the patient and physician alike and lead to undesirable peri- and post-treatment events. The delivery of surfactant in a gentler, non-invasive manner would empower physicians to provide improved life support and potentially a marked improvement in survival.
In the following, various prior art options for aerosol surfactant delivery are discussed. The delivery of pulmonary surfactant to treat lung diseases such as ARDS and respiratory distress syndrome, RDS, has been via the instillation of 20 to 80 mg/ml of suspensions of surfactant at doses generally ranging from 100 mg to 200 mg/kg or 100-700 ml for a 70 kg adult. Aerosolized surfactant may require a considerably lower dose ( 1/20) to achieve a similar physiological effect. It also eliminates the hypercapnia seen on bolus instillation. However, it is not yet part of the clinical armamentarium. This has been largely due to the difficulty of aerosolizing and delivering high concentrations of surfactant within a relatively short treatment time. In neonates, aerosolized surfactant was delivered over 3 hours. This situation is markedly exacerbated when attempting to deliver the same dose/kg of aerosolized surfactant to adults.
Mesh-type nebulizers generate soft mists through the creation of aerosols formed by liquids passing through an array of 2-3 μm diameter holes in a mesh. The energy to produce the aerosol is provided by electromechanical vibration of the mesh, or a horn located behind the mesh. A major drawback, however, is that the output of these nebulizers is limited by the viscosity of the nebulized formulation. Using low molecular weight polyols, it was demonstrated that the output markedly decreased or ceased when the viscosity was greater than 2 cSt (˜2 cSt). The output of surfactant from one such nebulizer known by the trade name Aeroneb has been reported to aerosolize 0.1 ml/min resulting in the delivery of just 3 mg/min of surfactant at its output.
While jet type atomizers can aerosolize more viscous solutions their output is generally reduced to about 0.3 ml/minute or less for particles sizes of about 3 μm mass median aerodynamic diameter, MMAD. Aerosol outputs of surfactant of up to 7 mg/min have been reported by using these jet type atomizers. In addition, jet type atomizers typically recirculate the fluid that is not presented at the output leading to increasing concentrations of the solute, sol or liposomal content resulting in increased viscosity, decreased output and a change in the particle size. In addition, foam created in by surface active agents in the atomizer can also dramatically inhibit aerosol formation.
A capillary aerosol generator has been reported to be used by Discovery Laboratories to deliver surfactant to neonates. In this generator the surfactant suspension is heated in a capillary tube and evaporated. The output aerosol comprises the particles condensed on nuclei when the vapor is cooled. Such devices have the potential to cause heat-induced surfactant degradation. This device can take over an hour to produce 100 mg of surfactant in aerosol form.
Recently surfactant has been reported to be delivered from dispersing a dry powder of surfactant. Delivery rates of 6.6 mg/min in 0.84 liters of air have been reported. However, the efficiency of the delivery system has not been reported and is considered likely very low.
From the U.S. Pat. No. 9,120,109 B2 aerosol generation from a nozzle is known comprising a fluid supply through a fluid supply orifice in close proximity to a plate, with the plate having an orifice of the same size as the fluid supply orifice. This proximity of the fluid supply orifice to the plate orifice was 0.1 to 0.25 times the diameter of these orifices. This patent further describes a transition from focused-flow (FF) to turbulent-flow-focusing (TFF) to flow-blurring (FB) and describes an observed reduction in particle size as the Reynolds number increases to what is likely a fully developed turbulent flow.
The aforementioned prior art technologies have not been shown to provide clinically relevant doses of surfactant to the adult respiratory tract, let alone to deliver a high mass in a short treatment time targeted at alveolar deposition. Therefore, these prior art technologies fall short on delivering certain drugs at the required delivery rate, for instance to treat ARDS and other respiratory diseases whose efficacy may depend on higher doses being delivered to the lungs in a shorter time span.